Environmental exposures to a wide array of natural toxins and man-made toxicants are often a consequence of military service; thus it is important to consider the long-term effects of such exposures on our Veterans and their offspring. In particular, our studies have shown that preconception exposures to endocrine disrupting agents can not only reduce both male and female fertility but also adversely affect pregnancy outcomes regardless of which parent had the toxicant exposure. Of equal relevance to historical military service patterns, we demonstrated in a murine model that the toxicant exposure history of the father can be a significant risk factor fo preterm birth (PTB) in his unexposed female partner. While a number of endocrine disrupting toxicants can negatively impact fertility and maintenance of pregnancy, TCDD (2,3,7,8-tetrachlorodibenzo-pdioxin or, commonly, dioxin) was a major contaminant of the Vietnam-era herbicide Agent Orange. As product of combustion, TCDD continues to be of concern since this toxicant has been documented in Iraq and Afghanistan in areas affected by oil fires and waste incineration. The studies proposed within this application will examine the role of paternal exposures to TCDD, focusing on the capacity of the placental phenotype to disrupt the action of progesterone at the maternal-fetal interface. Our preliminary studies indicate that the ability of TCDD to disrupt the anti-inflammatory action of progesterone during pregnancy allows this toxicant to act as both an endocrine and immune disruptor, significantly increasing the negative impact of this toxicant. More specifically, a past TCDD exposure in our murine model significantly increased the likelihood that inflammation associated with common infections would result in PTB. Since maternal infections are frequently identified in term deliveries, our proposal will focus on the toxicant exposure history of the father as a significant missing piece to understanding why maternal infection does not always pose a risk for adverse pregnancy outcomes. Furthermore, we will examine the potential that dietary/therapeutic modifications, which can be utilized by active military personnel, will protect their future reproductive health. Equally, important, we will assess the potential that a typical Western-style diet will further exacerbate the negative effects of a prior toxicant exposure. In order to address these issues, we will utilize both our established mouse model of spontaneous PTB and new models allowing oral and inhalation exposure routes. In vivo translation of the in vivo findings will be done using traditional co-culture systems with mouse and human stromal/decidual cells and cytotrophoblast cells. Lastly, we will establish a novel Maternal-Fetal Membrane on a chip (MFIchip) system that recreates the 3-dimensional structure of early human pregnancy. The MFIchip will translate our murine data to a model of early human pregnancy. We propose the following: Specific Aim 1: To identify inflammation-related biomarkers within the testis of TCDD-exposed male mice which correlate to alterations in placental-decidual function such that preterm birth occurs in their control mating partners. Specific Aim 2: To examine the impact of males with an environmentally relevant body burden of TCDD, with and without a secondary adult exposure, on pregnancy outcomes. Specific Aim 3: To translate our in vivo murine studies to the human condition using a unique human maternal fetal interface on a chip (MFIchip) system. Environmental toxicant exposure occurring within combat zones is an ancient problem; however, the recognition that such exposures may have negative consequences on both the short and long-term health of our Veterans is relatively new. Since reducing exposures in wartime is not realistic, this research project is focused on identifying strategies that it may enable us to protect our Veterans from the future reproductive risks posed by certain environmental toxicants.